The present invention relates to a process for the preparation of the enantiomeric forms of 2-substituted 2-(2,5-dioxoimidazolidin-1-yl)acetic acid derivatives of the formula I, wherein R1, R2 and R3 have the meanings given below, by stereodifferentiating conversion of mixtures of the enantiomers with the aid of enzymes.
The chiral acetic acid derivatives of the formula I, which carry a 2-(2,5-dioxoimidazolidin-1-yl) residue and a further substituent R2 in the 2-position of the acetic acid unit, are key building blocks or precursors for a range of potent active pharmaceutical ingredients as described, for example, in EP-A-918059 and its counterparts including U.S. Pat. No. 6,331,552, or in WO-A-99/60015 or WO-A-00/69831 and its counterpart U.S. Pat. No. 6,399,643. All of the aforementioned references are incorporated herein by reference. The active ingredients described in these documents are inhibitors of the adhesion and migration of leukocytes and/or antagonists of the integrin adhesion receptor VLA-4 and are suitable, for example, for therapy and prophylaxis of inflammatory disorders, for example rheumatoid arthritis, of allergic disorders or of asthma or atherosclerosis. For preparing active pharmaceutical ingredients which are present in stereochemically homogenous form at the chiral carbon atom in the 2-position of 2-substituted 2-(2,5-dioxoimidazolidin-1-yl)acetic acid unit, stereochemically homogeneous building blocks are used as starting materials which may first have to be synthesized in a complex manner from stereochemically homogeneous starting materials, or mixtures of stereoisomeric compounds have to be separated in a laborious manner, for example by chromatography. For the production of active pharmaceutical ingredients of this type on an industrial scale in particular, there is therefore a need for a simple and cost-effective route to the enantiomeric forms of the compounds of the formula I in sufficient enantiomeric purity (optical purity). An optical resolution or enantiomer separation of the racemic compounds of the formula I, which are obtainable in a simple way, for example, from the racemic 2-substituted 2-aminoacetic acid derivatives by formation of the hydantoin ring or by alkylation of the hydantoin with racemic 2-substituted 2-haloacetic acid derivatives, is hitherto unknown.
Surprisingly, it was found that, although an enzymatic optical resolution of compounds of the formula I by stereoselective hydrolysis of compounds wherein R3 has a meaning other than hydrogen does not succeed in a useful manner with a large number of enzymes, there nevertheless is a certain group of enzymes which provides the individual enantiomeric forms in pure form from mixtures of enantiomeric compounds of the formula I. Among the enzymes found to be unsuitable are, for example, lipases, in fact not only lipases of microbial origin and lipases from Candida spec. or Pseudomonas spec. but also lipases from the bovine or porcine pancreas. Just so proteases and peptidases such as subtilisin or pronase were found to be unsuitable for the enzymatic optical resolution of compounds of the formula I. Surprisingly, a sufficient conversion and a good stereoselectivity were only observed using esterases such as mammalian liver esterases or mammalian liver acetone powders, which allow the separation of enantiomeric mixtures of compounds of the formula I into their optically pure enantiomeric forms in a simple and efficient manner.